Epithelial to Mesenchymal Transition Is Activated in Metastatic Pheochromocytomas and Paragangliomas Caused by SDHB Gene Mutations

被引：96

作者：

Loriot, Celine ^{[1
,4
,9
]}

Burnichon, Nelly ^{[1
,2
,4
]}

Gadessaud, Noemie ^{[1
]}

Vescovo, Laure ^{[5
]}

Amar, Laurence ^{[1
,3
]}

Libe, Rossella ^{[4
,6
,7
,8
]}

Bertherat, Jerome ^{[4
,6
,7
,8
]}

Plouin, Pierre-Francois ^{[1
,3
,4
,8
]}

Jeunemaitre, Xavier ^{[1
,2
,4
]}

Gimenez-Roqueplo, Anne-Paule ^{[1
,2
,4
,8
]}

Favier, Judith ^{[1
,4
]}

机构：

[1] Paris Cardiovasc Res Ctr, INSERM, UMR 970, F-75015 Paris, France

[2] Hop Europeen Georges Pompidou, AP HP, Serv Genet, F-75015 Paris, France

[3] Serv Hypertens Arterielle, F-75015 Paris, France

[4] Univ Paris 05, Fac Med, F-75006 Paris, France

[5] Ligue Natl Contre Canc, Programme Cartes Identite Tumeurs, F-75013 Paris, France

[6] Inst Cochin Genet Mol, INSERM, CNRS, Dept Endocrinol Metab & Canc,U1016,UMR8104, F-75014 Paris, France

[7] Hop Cochin, AP HP, Ctr Reference Malad Rares Surrenale, Serv Malad Endocriniennes & Metab, F-75014 Paris, France

[8] Natl Canc Inst, Rare Adrenal Canc Network Cortico Medullosurrenal, F-75014 Paris, France

[9] Univ Paris Diderot, F-75205 Paris, France

来源：

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM | 2012年 / 97卷 / 06期

关键词：

SUCCINATE-DEHYDROGENASE; MALIGNANT PHEOCHROMOCYTOMA; SNAIL; SUSCEPTIBILITY; IDENTIFICATION; PROGRESSION; EXPRESSION; CARCINOMA; CADHERIN; TWIST;

D O I：

10.1210/jc.2011-3437

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Context: Pheochromocytoma and paraganglioma are rare neural-crest-derived tumors. They are metastatic in 15% of cases, and the identification of a germline mutation in the SDHB gene is a predictive risk factor for malignancy and poor prognosis. To date, the link between SDHB mutations and malignancy is still missing. Objective: Epithelial to mesenchymal transition (EMT) is a developmental event, reactivated in cancer cells to promote cell mobility and invasiveness. The aim of this study was to address the participation of EMT in the metastatic evolution of pheochromocytoma/paraganglioma. Design and Patients: Transcriptomic profiling of EMT was performed on 188 tumor samples, using a set of 94 genes implicated in this pathway. Activation of EMT was further confirmed at protein level by immunohistochemistry in a second set of 93 tumors. Results: Hierarchical unsupervised classification showed that most SDHB-metastatic samples clustered together, indicating that EMT is differently regulated in these tumors. Major actors of EMT, metalloproteases and components of cellular junctions, were either up-regulated (LOXL2, TWIST, TCF3, MMP2, and MMP1) or down-regulated (KRT19 and CDH2) in SDHB-metastatic tumors compared with nonmetastatic ones. Interestingly, within metastatic tumors, most of these genes (LOXL2, TWIST, TCF3, MMP2, and KRT19) also allowed us to discriminate SDHB-mutated from non-SDHB-related tumors. In the second set of tumors, we studied Snail 1/2 expression by immunohistochemistry and observed its specific nuclear translocation in all SDHB-metastatic tumors. Conclusion: We have identified the first pathway that distinguishes SDHB-metastatic from all other types of pheochromocytomas/paragangliomas and suggest that activation of the EMT process might play a critical role in the particularly invasive phenotype of this group of tumors. (J Clin Endocrinol Metab 97: E954-E962, 2012)

引用

页码：E954 / E962

页数：9

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